The purpose of this project is to investigate and define newly recognized mechanisms which are set in motion at the cellular level during the process of clotting and fibrinolysis and which participate in the regulation of fibrin removal. Studies planned for the coming year concern factors and events that accelerate fibrinolysis by increasing the availability of plasminogen activator (urokinase). Our concepts and approaches are based on our previous studies which showed that deposition of fibrin in tissue culture leads to increase in urokinase and rapid removal of fibrin and further that this increase is due to proteolytic enzymes which convert an inactive precursor in tissue to urokinase. Enzymes formed in the process of fibrinolysis as well as in that of clotting, i.e., plasmin and thrombin, appear to participate in and may regulate such conversion, plasmin by inducing and thrombin by "blocking" formation of urokinase from precursor. We expect to elucidate these events, extend our investigation to other clotting factors and their inhibitors, clarify aspects of the production and release of urokinase precursor in human tissues, conversion to urokinase ("spontaneous" and experimentally induced), presence in tissues of native inhibitors of precursor and its activation and the role of these various factors in physiological and excessive fibrinolysis.